Submissions for variant NM_015272.5(RPGRIP1L):c.3562G>A (p.Val1188Met)

gnomAD frequency: 0.00052  dbSNP: rs142317242

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232122	SCV000290126	likely benign	Familial aplasia of the vermis; Meckel-Gruber syndrome	2025-02-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000302183	SCV000397754	uncertain significance	Nephronophthisis 8	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000359252	SCV000397755	uncertain significance	Meckel syndrome, type 5	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000271829	SCV000397756	uncertain significance	Joubert syndrome 7	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV004955360	SCV005488034	likely benign	Inborn genetic diseases	2024-07-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Natera, Inc.	RCV001271323	SCV001452408	uncertain significance	Familial aplasia of the vermis	2020-04-24	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532945	SCV004116662	uncertain significance	RPGRIP1L-related disorder	2024-09-04	no assertion criteria provided	clinical testing	The RPGRIP1L c.3562G>A variant is predicted to result in the amino acid substitution p.Val1188Met. This variant was reported in the compound heterozygous state in a patient with subcortical heterotopia; however, pathogenicity was not established (Uzquiano et al. 2019. PubMed ID: 31390572). This variant is reported in 0.21% of alleles in individuals of European (Finnish) descent in gnomAD, which is significantly more common than other known pathogenic variants in RPGRIP1L. Although we suspect this variant may be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.